Heparin is known to have antithrombotic, anticoagulant, and antiproliferative effects. We hypothesized that chronic subcutaneous and/or direct intramural administration of heparin would reduce restenosis and inhibit plaque growth following balloon angioplasty. Focal atherosclerosis was induced bilaterally in the femoral arteries of 59 rabbits by air desiccation intimal injury and a 2% cholesterol diet. After angioplasty, the rabbits were assigned to one of four treatment groups. Control arteries (n=21) received no additional heparin. A second group of 20 arteries was treated with a porous balloon which delivered heparin (1500 U) directly into the arterial wall. A third group (n=29) received subcutaneous heparin (350 U/kg/day) for 28 days, and a fourth group (n=23) was treated with subcutaneous and intramural heparin. Chronic subcutaneous heparin after balloon angioplasty results in a modest reduction in angiographic restenosis in this model, however, the absolute luminal diameter is not improved compared with pre-angioplasty and plaque area and percent luminal narrowing by plaque were not different among the four treatment groups. Heparin can be delivered into an atherosclerotic plaque using a porous balloon, but this treatment does not reduce restenosis after angioplasty in this model.